The Kell blood group is composed of two proteins, Kell and XK, linked by a single disulfide bond. Kell is a 93 kDa type II membrane glycoprotein and XK a 50.9 kDa protein that traverse the membrane ten times. Kell protein exists in many polymorphic forms and some of its antigens are highly immunogenic and can cause severe reactions if mismatched blood is transfused. Maternal alloimmunization to Kell antigens can also cause fetal and neonatal anemia. Recent studies from our laboratory demonstrated that Kell is an enzyme that activates the endothelins and has marked preference for endothelin-3. The endothelins are potent vasoconstrictors and are also involved in developmental processes. The function of XK is not known but its absence, the McLeod phenotype, is associated with red cell acenthocytosis and late onset forms of muscular and neurological abnormalities. Our objectives are to define the define the physiological functions of the Kell/XK complex and to determine the cellular mechanisms by which antibodies to kell elicit fetal and neonatal anemia. Recent studies from our laboratory demonstrated that Kell is an enzyme that activates the endothelins and has marked preference for endothelin-3. The endothelins are potent vasoconstrictors and are also involved in developmental processes. The function of XK is not known but its absence, the McLeod phenotype, is associated with red cell acanthocytosis and late onset forms of muscular and neurological abnormalities. Our objectives are to define the physiological functions of the Kell/XK complex and to determine the cellular mechanisms by which antibodies to Kell elicit fetal and neonatal anemia. To achieve our objectives we have three specific aims. 1. To identify the domains of Kell that are necessary for substrate and enzymatic specificity and to compare the enzymatic properties of wild-type Kell to those of KEL1 and KEL6. The KEL1 and KEL6 polymorphisms have distinctive distributions in persons of African heritage, as compared to Caucasians, and may have developed due to selective pressures. 2. To determine the complementary roles of Kell and XK proteins, by studying targeted disruption of the Kell and XK loci and mice. 3. To determine the mechanisms by which antibodies to Kell suppress erythropoiesis, with emphasis on the interactions of Kell antibodies with nascent Kell antigens that occur on erythroid progenitor cells.